Modem drug development relies on the rapid synthesis of small organic molecules (drug candidates) by using combinatorial chemistry methods. Solution phase combinatorial chemistry methods are increasingly important, and the fluorous technology platform is a new and powerful addition that both expedites and leverages solution phase synthesis. However, the utility of new techniques like fluorous synthesis and fluorous mixture synthesis is currently limited by the dearth of commercially available fluorous tags (protecting groups), so new fluorous tags are urgently needed. This SBIR proposal addresses this need through a stepwise process of research (discovery) and development (validation and scale up) of new fluorous tags. The specific aims are: 1) To synthesize fluorous variants of Fmoc (9-fluorenylmethylcarbamate), Cbz (benzyl carbamate) and Bn (benzyl) protecting groups. The new fluorous tags are designed such that the perfluoroalkyl chains will control the separation properties of tagged molecules on fluorous silica. One of more methylene groups may be incroporated to offset the electronic effect of the periluoroalkyl groups. 2) To validate the use of these new fluorous tags in a synthetic sequence involving protection, reaction and deprotection. For each fluorous group, several candidates will be tested prior to selecting the one(s) that mimics the parent well in protection and deprotection and have suitable separation properties on fluorous silica. 3) To optimize process scale syntheses of the new fluorous tags and to synthesize homologs. The synthesis of these new tags will be optimized on 100-200 gram scale. As needed, the company will contract for the kg scale preparation of these new tags with custom synthesis companies. For each of these fluorous tags, a series of homologs with variable number of fluorines will be synthesized for the use in fluorous mixture synthesis.